Hypersensitivities

General Information (Abbas pp 201)

Immune responses are considered to defend the host against infections. Sometimes, immune responses are themselves capable of causing tissue injury and disease. There are two main types of hypersensitivities:

1) an immune response towards a foreign antigen that is uncontrolled and dysregulated,

2) immune responses can be directed against self antigens – therefore tolerance is reduced/impaired.

Type I Hypersensitivity – Humoral – 2-30 mins (Abbas pp 202, Fig 11-1)

These types of hypersensitivities are also called allergies. Individuals that develop such reactions are said to be “atopic”. It often follows inflammation and results in the production of IgE. This triggers release of mediators from mast cells. It is important to note, that for immediate hypersensivity reactions to occur – the host must have had previous exposure to the antigen. Common types of Type I reactions include: hay fever, food allergies, bronchial asthma, and anaphylaxis.

Steps in immediate hypersensitivity (Abbas pp 202)

Production of IgE antibody

• Normal individuals do not mount a strong TH2 response to most foreign antigens. For some unknown reason, some individuals mount this abnormally sensitive response

• Immediate hypersensitivity therefore develops when an “atopic” individual is exposed to an allergen (protein antigens) ≫ causes the activation of TH2 cells.

• TH2 begin secreting cytokines. Of these, Il-4 & IL-13 stimulate B lymphocytes specific for the particular foreign antigen to start producing IgE antibodies.

• “Atopic” individuals begin to produce large amounts of IgE compared to normal individuals. It has been established that “atopy” has a genetic link.

Activation of Mast cells and secretin of mediators

• Once IgE is produced in response to a particular allergen, it binds to the FcRI receptors expressed on the cell membrane of mast cells. The mast cells are now coated with IgE antibody that is specific that particular allergen. This coating process is called “sensitisation” because now the mast cells are sensitive (“loaded” with IgE) to activation upon contact with that allergen.

• Mast cells are present in all connective tissues of the body, so which mast cells are activated depends on the route of entry of the allergen.

• Thus, when the allergen presents again at a later stage the mast cells get activated. This occurs due to binding of the allergen to 2 or more IgE antibodies on the mast cell.

• This causes IgE and Fc receptors (carrying the IgE) to cross link. This triggers biochemical signals from signal transducing chains of the FcRI receptor. This causes the production of mediators.

• The most important of these mediators are: vasoactive amines (i.e: histamine) and proteases released from granules, products of arachidonic acid metabolism and cytokines. For fⁿ of these mediators refer to: Abbas pp 205. Generally, mast cell mediators cause acute vascular and smooth muscle reactions + inflammation.

• The cytokines produced by the mast cells stimulate leukocytes to be activated  late phase reaction. The leukocytes are: eosinophils + neutrophils (both stimulated by TNF and IL-4), and TH2 cells. Chemokines produced by mast cells and tissue cells also cause leukocytic recruitment. TH2 cells can further release cytokines which exacerbate the reaction.

The dose and route of allergen administration determines the type of IgE-mediated allergic reaction that results. I.e.: Whether it is serious or not so serious.

The allergen can enter the body via 1 of 4 ways:

• Intravenously, directly into the blood stream (i.e.: injected drugs, snake bites)

• Subcutaenously – low dose

• Inhalation – low dose

• Ingestion

All Immediate hypersensitivity reactions require mast cell activation upon a re-presentation of that particular allergen. Mast cells are found throughout the body. Generally, they are divided into mast cells associated with blood vessels and those found in connective tissue. In an allergic individual, all of these cells are loaded with IgE antibodies. Thus, the allergic response initiated upon re-presentation depends on which mast cells are activated. Allergen administration intravenously results in systemic histamine release due to systemic mast cell activation, subcutaneous administration results in local inflammatory reaction, inhalation causes mucosal mast cell activation resulting in excess mucous produced, and smooth muscle contraction of lower airways. Ingestion of an allergen activates gut mucosal mast cells, therefore smooth muscle contraction ≫ vomiting. The allergen is also absorbed into the blood ≫ back to intravenous administration.

Detection / Therapy for Immediate Hypersensitivity (Abbas pp 208)

Detection is simply done by skin test, RIST test (for IgE levels) and RAST (for antigen specific IgE levels). Therapy is aimed at inhibiting release of mediators of mast cells, inhibiting effects of mast cell mediators, and reducing inflammation. Firstly, you remove the allergen causing the allergic reaction. Commonly used drugs include: anti-histamines (hay fever), bronchial smooth muscle relaxants, adrenaline (anaphylaxis), corticosteroids (anti-inflammatory). Repeated administration of the allergen in small doses makes the host desensitised ≫ de-sensitisation/hyposensitisation.

Category: Pathology Notes